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Indiana University

Battling Dementia in the Elderly

Ghetti, professor of neuropathology at the Indiana University School of
Medicine in Indianapolis, receives about fifty brains per year from across the
United States. The brains are brown on the outside, partially a result of the
formalin in which they are preserved, but not what one would expect after
constantly hearing them referred to as "gray matter." Inside, they are off-
white, the color of three-day-old snow on the side of a road.

Under the microscope, a brain slice looks like a strange landscape seen from
the space shuttle, with tiny black specks that could be ponds and larger red
splotches--forests, maybe--and an occasional river sweeping across the
terrain. There's a wondrous flow to the whole that is quite beautiful.
Beautiful, that is, in the way a mushroom cloud is beautiful, if its form is
detached from the horrifying reality of what is actually happening.
For the brains Ghetti analyzes belonged to people who were afflicted with
dementia when they died. Dementia is a gradual deterioration in mental
functioning marked by memory loss as well as impairment in at least one other
area of cognition.

Alzheimer's Disease

The most common form of dementia--and perhaps the most insidious--is
Alzheimer's disease. The first symptom of illness is occasional short-term
memory loss, followed by difficulties in acquiring new information, performing
routine tasks (such as driving), or making sound decisions.

In the later stages of Alzheimer's disease, which occur years after the onset
of initial symptoms, patients experience profound memory loss (short and long
term) along with widespread disability. They may become disoriented and
severely depressed, lose control over bodily functions, and fail to recognize
loved ones or even remember who they themselves are.

As the wife of an Alzheimer's disease victim once told a Congressional
committee, the experience is like "a funeral that never ends." The memories,
the minds, the very identities of patients slowly pass away while the body
lives on.

These symptoms are linked to several characteristic
brain
abnormalities--
the kind that Ghetti sees when he examines brains after death. Among them are
(a) loss of neurons, or brain cells; (b) plaques, or deposits of
a substance called beta-amyloid, between neurons; and (c) tangles inside
neurons composed of a protein called tau.

At present, Alzheimer's dementia afflicts between 3 and 4 million Americans,
most of them over the age of sixty-five. In fact, the older a person gets, the
greater his or her chances of getting the disease. At sixty-five, the odds of
having Alzheimer's disease are less than one in fifty. By eighty-five, those
odds have risen to as high as one in two. Since the number of Americans over
eighty-five is projected to double or even triple over the next thirty years,
the prevalence of Alzheimer's disease will increase dramatically, placing
tremendous burdens on families and the U.S. health care system.

Unfortunately, the cause of Alzheimer's disease is unknown. The disease is
difficult to diagnose, particularly in its early stages. And there is no known
cure.

The Alzheimer Disease Center

Fortunately, that all may be changing, thanks in part to Ghetti and some of
his colleagues at the Indiana University School of Medicine. Ghetti is
director of the Indiana Alzheimer Disease Center, which is funded by a large
grant from the National Institute on Aging. The Center's purpose is to
facilitate the development of a well-documented population of Alzheimer's
patients for clinical and pathological studies. The Center also supports
outreach programs to keep doctors and other community members informed of
recent advances in Alzheimer research.

One of Ghetti's key associates is Martin Farlow, associate professor of
neurology, who directs the Center's outpatient clinics. Ghetti and Farlow have
collaborated on studies of hereditary forms of Alzheimer's syndrome and with
other dementias, including Gerstmann-Straussler-Scheinker disease. Farlow has
also investigated various drugs that may prove useful in treating senile
dementia. Dr. Merrill Benson (Medicine), Dr. Michael Conneally (Medical and
Molecular Genetics), Dr. Steven Dlouhy (Medical and Molecular Genetics), Dr.
Hugh Hendrie (Psychiatry), and Dr. Debomoy Lahiri (Psychiatry) are among the
many other IU faculty involved in the Alzheimer's research.

A different grant by the National Institute on Aging is supporting the
research of yet another faculty member, Joe Christian, chair of the Department
of Medical and Molecular Genetics. Christian is collaborating with scientists
from several other universities on a study of
aging twins to
try and
understand the roles that heredity and the environment play in the development
of Alzheimer's disease.

Genetic and Environmental Factors

Some of the most exciting progress in medical research in recent years has
involved the identification of defective genes that make people susceptible to
particular diseases. Osteoporosis, cancer of the colon, Huntington's disease,
Lou Gehrig's disease: almost weekly, it seems, scientists zero in on a gene
associated with another debilitating illness.

Now Alzheimer's disease may be joining that list. Over the years, scientists
have identified several dozen families around the world in which a form of
Alzheimer's disease characterized by early onset (in one's forties) passes
from generation to generation. As it happens, one of these families lives in
Indiana. Three years ago, Benson, Farlow, Ghetti, and their colleagues
discovered that Alzheimer's disease in this family was associated with a
mutation on a particular gene, the amyloid precursor protein (APP) gene,
located on chromosome 21 (the one involved in Down's syndrome).

To be sure, finding an association between two phenomena does not prove
that one causes the other. But Farlow is confident that there is a
cause/effect relationship. "In this family the evidence would clearly indicate
that this mutation, this change in the gene, somehow is causing the disease to
occur," he says. He is not sure exactly how it happens, but apparently the
mutation disrupts the process by which the large amyloid precursor protein
breaks down into the smaller beta-amyloid protein, leaving behind an insoluble
form of beta-amyloid that accumulates in plaques in the brain.

This connection between the APP gene mutation and familial Alzheimer's disease
was only the second ever to be reported in the world's scientific literature.
Over the past three years, similar mutations have been found in a few other
families with early-onset forms of Alzheimer's disease. Ghetti, Farlow,
Dlouhy, and Karen Hsiao, a colleague from the University of California, San
Francisco, have also discovered a mutation on a different gene that causes a
rare form of dementia called Gerstmann-Straussler-Scheinker disease (see sidebar The
Frontier of
Pathology).

Although no such gene mutations have been found in the most common form of
dementia--nonfamilial, late-onset cases of Alzheimer's disease--available
evidence suggests that genetic predisposition may be the cause here as well.
Studies have shown, for example, that parents, siblings, and children of
people with Alzheimer's have a 50 percent chance of developing the disease if
they live to their late eighties--"just what you would expect if a single gene
were the cause," says Christian. Still, this evidence is far from conclusive.
"Neither the linkage studies in familial Alzheimer's disease nor the family
history investigations of other cases can answer many questions about the
roles of genes and the environment or their interaction," Christian and his
colleagues write.

There may be a way to answer some of those questions, suggests Christian: twin
studies. The method is relatively simple, in theory at least. Compare
identical twins (those who came from the same egg and therefore have the same
genetic material) with fraternal twins (those who came from two different
eggs).

If Alzheimer's disease is genetic in origin, and if one identical twin has it,
the other should eventually get it as well. In other words there should be 100
percent concordance among identical twins, compared with 50 percent for
fraternal twins. Also, if one identical twin gets Alzheimer's disease at, say,
age seventy-eight and the other doesn't get it until age eighty-six, then
researchers may be able to identify environmental factors that can delay the
onset of the disease.

Unfortunately, because of logistical problems, most twin studies to date have
been small and inconclusive. In a major advance over these studies, a group of
researchers at Duke University is investigating Alzheimer's disease in a very
large group of twins: the National Academy of Sciences registry of aging twin
veterans. The registry comprises about 8,000 pairs of male twins born between
1917 and 1927 who have served in the U.S. military. It is a veritable gold
mine, not just for studies of dementia but for other diseases and
characteristics of aging as well. Christian serves on the National Academy of
Sciences study committee that oversees the twin registry and is a consultant
to the Duke investigators.

Out of this mine, forty Alzheimer patients have been identified with an
identical twin and sixteen with a fraternal twin. Preliminary studies indicate
that the current concordance rate for the identical twins is 35 percent. None
of the fraternal twin pairs is yet concordant. Of course, the subjects are
still relatively young for an Alzheimer's study--sixty-seven to seventy-seven
years old. As they move into their eighties and nineties, the study should
contribute to an improved understanding of genetic and environmental factors
in nonfamilial Alzheimer's disease.

Diagnosis

At present, the only way to determine if someone has Alzheimer's disease is to
rule out all other possible causes of dementia, such as strokes, brain tumors,
and severe depression. If none of these is at fault, the patient probably has
Alzheimer's, although one can't be absolutely certain until the brain is
examined after death.

Following up on leads from previous studies, Farlow and Ghetti took samples of
cerebrospinal fluid from the Indiana early-onset family members who were known
to have the disease or to be carrying the gene."What we found," Farlow
explains, "was that in affected patients in this family, the level of the
soluble form of the amyloid precursor protein was low, and in patients who
were gene carriers, the level seemed to be intermediately low, a little bit
decreased from normal but not as low as the patient who was already affected."

What this all suggests is the exciting possibility that levels of the amyloid
precursor protein in cerebrospinal fluid may prove to be a marker for
Alzheimer's disease, assisting diagnosis.

Treatment

Ultimately, of course, the goal of all Alzheimer research is not just to
understand the disease and diagnose it, but to treat it. One promising area of
research involves neurotransmitters, or chemicals that transmit signals from
one brain cell to another. Alzheimer patients have low levels of many
neurotransmitters, including one called acetyl-choline. This deficiency may be
responsible for some of the deficiencies in memory and cognitive functioning.
Farlow has been investigating the effects of several drugs that boost levels
of acetylcholine.

One such drug is called Tacrine. "Tacrine functions by inhibiting an enzyme
that breaks down acetyl-choline," explained Farlow. "And if you inhibit its
breakdown, what little is there in the brain will stay around longer, so
effectively you'll get higher levels." The results of a series of studies have
been promising. "It has been found," he says, "that Tacrine does improve
memory and cognition in some patients with Alzheimer's disease--not all
patients but in some patients. The effect appears to be mild, but it is
definite." At present, Tacrine is the only drug that has been approved for
physicians to prescribe for senile dementia.

Future Prospects

Several months ago on the front page of the Indianapolis Star, a doctor
from Duke University proclaimed, "I am absolutely convinced that within ten
years we will have a pill that prevents Alzheimer's disease." Farlow is not
quite so sanguine about the prospects of Alzheimer research, but he believes
that at the very least, significant progress will soon be made in diagnosing
Alzheimer's disease, delaying onset of the disease, and treating the disease's
symptoms. "I think research may lead to tests which accurately will determine
what an individual's risk of developing the disease is, or at what age they
may be at great risk for the disease." he says. "I think it is possible that
we may identify risk factors in the future that, if avoided, will delay onset
of Alzheimer's disease."

Or drugs may be developed that will delay onset. "If you can raise that age of
onset enough," Farlow says, "then you can tremendously mitigate the effects of
this illness on the population. Finally, we will continue to search for better
drugs to treat Alzheimer's when it does strike."

Even if Alzheimer's is brought under control, the battle against other forms
of dementia will no doubt continue. To wit, Ghetti got a brain in the mail
recently--this one from Texas--which, as far as he could tell, did not fit any
known classification of dementia. "It's a new disease," he says. There is no
telling what gene or protein or as-yet-undiscovered agent is responsible or
what suffering it may cause. But with Ghetti, Farlow, Christian, and their
colleagues from the Indiana University School of Medicine on its trail, you
can bet the disease will yield its secrets before long.